Novel intranasal delivery of therapeutic agents using nanoparticles to treat leptomeningeal carcinomatosis

Dr. Yakir Rottenberg, Oncologist and Geriatric Clinic, Hadassah Univ. Hospital

Leptomeningeal carcinomatosis (LC) is a fatal clinical condition that affects 3% to 5% of all patients with solid tumors or approximately 45,000 to 75,000 patients in the U.S.A. alone. It is an increasingly common complication of cancer, notably, breast cancer (17.7%), lung cancer (25.8%), and melanomas (8.9%).

These tumors can metastasize to the brain causing LC. The dismal prognosis of patients diagnosed with LC stems from the poor penetration of anti-cancer therapeutics through the blood brain barrier (BBB). The BBB is a barrier that protects the brain from potentially harmful substances in the blood circulation. Treatment with chemotherapy is limited partially due to the inadequate penetration of therapeutic agents through the BBB so that the target can be reached. Thus, it is essential to develop the technology to target drugs to the brain safely.

Dr. Yakir Rottenberg in collaboration with Prof. Avi Domb from the School of Pharmacology are ready to carry out a very novel research where they will use the intranasal olfactory route (such as the nose spray) to bypass the BBB and have direct access to the brain for the noninvasive delivery of therapeutic agents. They will be using nanoparticles (virus size molecules) of a certain size and surface properties as well as fast elimination of the carrier for safe and effective drug administration to the brain. Nanotechnology is becoming one of the most promising sciences of the future for seeking cancer cells and delivering the chemicals to destroy them. The goal is to have nanoparticles attached to chemotherapeutic drugs and allow them to infiltrate the BBB for treatment. Dr. Rottenberg and research team have already carried out a proof-of-principle investigation in a mouse model for trytotropin-releasing hormone (TRH); TRH stimulates the release of the thyroid-stimulating hormone and has an anticonvulsant effect. The results of this study indicate that the intranasal delivery of TRH could be a viable means to suppress temporal lobe seizures and perhaps other seizure disorders. This technique can help develop and improve anticonvulsant drug delivery to the brain through the nasal route.

With sufficient financial support, Dr. Rottenberg and research team plan to use mouse models of breast cancer and use nanoparticles to serve as customized, precision drug targeting vehicles carrying large doses of chemotherapeutic agents into malignant cells while sparing healthy cells. They propose to use Paclitaxel which is one of the most effective chemotherapeutic drugs and lipid-based nanoparticles which is one of the promising drug-delivery candidates. In addition, they will have state-of-the-art imaging methods such as MRI and advanced mathematical modeling approaches for detailed quantities of the nanoparticles’ disposition, potential toxicities and efficacy after intranasal administration.

This investigation represents a very important stepping stone towards acquiring a basic understanding of the delivery process of nanoparticles loaded with therapeutic agents through the nasal route. The holy grail of this research encompasses the future development of nanoparticles loaded with other anti-cancer regimens with minimal potential danger in conjunction with maximal efficiency.